RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis.

Barrier dysfunction of the urinary bladder is postulated to contribute to patient morbidity in the bladder inflammatory disease interstitial cystitis (IC). IC is often considered a neurogenic cystitis, but the mechanisms underlying barrier dysfunction are unclear. In murine neurogenic cystitis induced by pseudorabies virus (PRV), we previously observed formation of urothelial lesions characterized by urothelial apoptosis and urothelial discontinuities. Lesion formation was preceded by mast cell trafficking to the lamina propria, and trafficking was mediated by tumor necrosis factor-alpha (TNF). Here, we found that supernatants of TNF-treated urothelial cultures promoted chemotaxis of bone marrow-derived mast cells in vitro that was blocked by anti-RANTES antibodies but unaffected by anti-TNF antibodies. In vivo, PRV infection of wild-type mice induced RANTES expression in the urothelium that was temporally coincident with lamina propria mast cell accumulation (maximum at days 3-4 following infection) and was not induced in TNF(-/-) mice, TNFR1/2(-/-) mice, or mice treated with anti-TNF antibodies. Anti-RANTES antibodies blocked PRV-induced lamina propria mast cell accumulation 56% and reduced the prevalence of animals with detectable lesions 42%, relative to isotype control antibodies. Bladder barrier function was quantified by measuring transepithelial resistance (TER). PRV induced a 49% loss of TER in the presence of control antibodies, but mice treated with anti-RANTES antibodies exhibited reduced TER loss (16%, P < 0.01). These data demonstrate that RANTES plays a key role in the pathogenesis of neurogenic cystitis and suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.

MASTering the immune response: mast cells in autoimmunity.

Mast cells are established participants in allergic disease and in protection against extracellular parasites. Recently, it has become apparent that mast cells exert many profound effects on a variety of both innate and adaptive immune responses. Using mast cell-deficient WBB6F1/J-kitW/kitWv (W/Wv) mice, we have demonstrated that mast cells are critical for severe disease in a murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). Reconstitution of the mast cell population in the periphery, but not the CNS, restores EAE severity. Mast cells exert their effects at both the inductive and effector phases of disease. EAE is mediated by autoreactive T cells that enter the CNS and initiate inflammatory responses, leading to demyelination within the spinal cord and brain. Although there are no intrinsic defects in W/Wv-derived T cells, both CD4+ and CD8+ autoreactive T cell responses are attenuated during early disease in W/Wv mice. Thus mast cells are essential for the optimal priming of autoreactive T cells. The entry of encephalitogenic T cells into the CNS is compromised in these mice as well. The effects on early T cell responses are due, in part, to the reduced percentage of activated dendritic cells in the lymph nodes of W/Wv mice after disease induction compared with wild-type mice. The finding that mast cells can alter T cell responses in EAE has much broader implications for understanding the impact of these cells on all T cell-mediated responses.